CANDIDATE: My research background and experiences have provided the groundwork for a career as a physician scientist. My clinical training in endocrinology and my basic science background and graduate training in immunology give me the unique opportunity to focus my research in the intersection of immunology, endocrinology, and metabolism. I am particularly interested in how protein hormones affect immunity. My goal over the next five years is to receive the ongoing mentoring and training necessary for a career as an independent investigator. During this time I will receive additional mentoring and training in Dr. Jeffrey Rathmell's laboratory, where I will develop new skills in lymphocyte biology, metabolism, and transgenic mouse technology. Dr. Michael Freemark, Chief of the Pediatric Endocrine division, will serve as my academic mentor and research consultant. My objectives for the next five years include the following: (1) advance my scientific abilities and skills in the areas of lymphocyte biology, metabolism, and the use of small animal models; (2) publish in high-quality, peer-reviewed scientific journals and present my data at national meetings; (3) obtain the experience and scientific knowledge necessary to transition towards independence; and (4) prepare a successful application for an independent investigator award before the end of the five year granting period. ENVIRONMENT: The Department of Pediatrics at Duke University Medical Center is dedicated to training academic physician-scientists to conduct research that will promote the health and well-being of children, and therefore offers an environment rich in resources for the junior investigator. These resources include a mentoring committee, an Office for Faculty Development, open collaboration between University departments, and state-of-the-art laboratories and animal housing facilities. Additional membership in the Stedman Nutrition and Metabolism Center and weekly seminars with other faculty across several departments will provide intellectual stimulation to promote critical thinking and scientific discussion. RESEARCH: Nutritional deprivation compromises immune function by decreasing cell-mediated and humoral immunity, phagocyte function, complement activation, and cytokine production. Deficits in adipose tissue, as seen in malnutrition, lead to a deficiency of the adipose hormone leptin, which plays a critical role in metabolic regulation as well as the development of immune function. Leptin-deficient individuals have a decrease in both total T and CD4 T cell number along with abnormal T cell function, making them more susceptible to intracellular infections and atopic disease, while administration of recombinant leptin protein reverses both the metabolic defects and immune abnormalities. The mechanisms by which leptin regulates lymphocyte number and function are not completely understood. Preliminary data suggest that leptin's effects on T cell function require activation of the T cell by signaling at both the T cell receptor (TCR) and co-stimulatory membrane protein CD28; that leptin activates the metabolic mediator AMP-activated protein kinase (AMPK) in lymphocytes; and that leptin is necessary for glucose uptake in activated cells. For these reasons, we hypothesize that the effects of leptin on lymphocyte number and function require full T cell stimulation and are mediated in part by leptin's effects on cellular metabolism. To test this hypothesis, we propose the following specific aims: (1) We will identify the signals required to allow T cells to become sensitive to leptin; (2) we will test the hypothesis that leptin increases cellular energy by activating glucose uptake and metabolism, and that AMPK activation is an important mediator of glucose metabolism following leptin stimulation in T cells; and (3) we will test the hypothesis that leptin signal is important for optimal peripheral T cell function and metabolism in vivo. The results of these studies should provide new insight into the mechanisms by which leptin regulates lymphocyte number and function, and may yield new approaches to the pathogenesis and treatment of immune dysfunction in nutritional disorders. PUBLIC HEALTH RELEVANCE: The nutritional status of an organism affects immune function. Malnutrition is associated with increased risk of infection and increased risk of death from serious infectious illnesses. The hormone leptin, which is secreted by fat cells in proportion to fat mass and affects immune function, may be responsible for linking nutritional status with immune cell function.